Methods and compositions for the treatment of eye diseases

ABSTRACT

Method and compositions for prophylaxis and/or treatment of diseases of the eye using antagonists of the integin receptors α v β 3  and/or α v β 5 . The compositions can be nanoparticles and are administered to the eye by injection into the subTenon&#39;s space of the eye.

TECHNICAL FIELD

The present invention relates generally to the field of medicine, andrelates specifically to methods and compositions for the prophylaxisand/or treatment of diseases of the eye using antagonists of the integinreceptors α_(v)β₃ and/or α_(v)β₅. More specifically, the inventionrelates to methods and compositions for the prophylaxis and/or treatmentof diseases of the eye using antagonists of the integrin receptorsα_(v)β₃ and/or α_(v)β₅ wherein the compositions are administered to theeye by subTenon's injection.

BACKGROUND

Integrins are a class of cellular receptors known to bind extracellularmatrix proteins, and therefore mediate cell-cell and cell-extracellularmatrix interactions, referred generally to as adhäsion events. Integrinsreceptors constitute a family of proteins across membranes with sharedstructural characteristics heterodimeric glycoprotein complexes formedof α and β subunits.

One class of integrin receptors, the vitronectin receptor, named for itsoriginal characteristic of preferential binding to vitronectin, is knownto refer to three different integrins, designated. α_(v)β_(1,) α_(v)β₃and α_(v)β₅Horton, Int. J.

Exp. Pathol., 71:741-759 (1990). α_(v)β₁ binds fibronectin andvitronectin. α_(v)β₃ binds a large variety of ligands, including fibrin,fibrinogen, laminin, thrombospondin, vitronectin, von Willebrand'sfactor, osteospontin and bone sialoprotein I. α_(v)β₅ binds vitronectin.The specific cell adhesion roles these three integrins play in the manycellular interactions in tissues is still under investigation, but it isclear that there are different integrins with different biologicalfunctions.

One important recognition site in the ligand for many integrins is thearginine-glycine-aspartic acid (RGD) tripeptide sequence. RGD is foundin all of the ligands identified above for the vitronectin receptorintegrins. This RGD recognition site can be mimicked by polypeptides(“peptides”) that contain the RGD sequence, and such RGD peptides areknown inhibitors of integrin function.

Integrin inhibitors containing the RGD sequence are disclosed, forexample, in EP 0 770 622 A2. The compounds described inhibit inparticular the interactions of β₃- and/or β₅-integrin receptors withligands and are particularly active in the case of the integrinsα_(v)β₃, α_(v)β₅, and α_(II)β₃, but also relative to α_(v)β₁, α_(v)β₆and α_(v)β₈ receptors. These actions can be demonstrated, for example,according to the method described by J. W. Smith et al. in J. Biol.Chem. 265, 12267-12271 (1990). In addition, the compounds possessanti-inflammatory effects.

On basis of integrin inhibitors containing the RGD sequence a multitudeof antagonists without the RGD sequence have been made available. Thoseintegrin inhibitors without RGD sequence are disclosed, for example, inWO 96/00730 A1, WO 96/18602 A1, WO 97/37655 A1, WO 97/06791 A1, WO97/45137 A1, WO 97/23451 A1, WO 97/23480 A1, WO 97/44333 A1, WO 98/00395A1, WO 98/14192 A1, WO 98/30542 A1, WO 99/11626 A1, WO 99/15178 A1, WO99/15508 A1, WO 99/26945 A1, WO 99/44994 A1, WO 99/45927 A1, WO 99/50249A2, WO 00/03973 A1, WO 00/09143 A1, WO 00/09503 A1, WO 00/33838 A1.

DE 1970540 A1 disclose bicyclic aromatic amino acids acting as integrininhibitors of the α_(v) integrin receptors, particulary of the integrinsα_(v)β₃ and α_(v)β₅. The compounds are very particularly active asadhesion receptor antagonists for the vitronectin receptor α_(v)β₃ Thiseffect can be demonstrated, for example, by the method described by J.W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271(1990).

WO 00/26212 A1 discloses chromenone and chromanone derivatives acting asintegrin inhibitors of the α_(v) integrin receptors, particulary of theintegrins α_(v)β₃ and a The compounds are also very particularly activeas adhesion receptor antagonists for the vitronectin receptor α_(v)β₃.

Integrin inhibitors have been suggested as pharmaceutically activeprinciple in human and veterinary medicine, in particular for theprophylaxis and treatment of various disorders. Specifically suggestedhave been their use for the treatment and prophylaxis of thecirculation, thrombosis, cardiac infarction, arteriosclerosis,inflammations, apoplexy, angina pectoris, tumor disorders, osteolyticdisorders, especially osteoporosis, angiogenesis and disorders resultingfrom angiogenesis, for example diabetic retinopathy of the eye, maculardegeneration, myopia, ocular histoplasmosis, rheumatic arthritis,osteoarthritis, rubeotic glaucoma, and also ulcerative colitis, Crohn'sdisease, multiple sclerosis, psoriasis and restenosis followingangioplasty.

Eye diseases resulting from angiogenesis are the leading cause of visualloss in America. While in case of the population of the age of over 65visual loss is predominantly effected by age-related maculardegeneration (AMD) in case of population of the age of less than 65 thisis predominantly effected by diabetic retinopathy.

In Wall Street Journal from Mar. 6 th, 2000 an overview about occurenceand current therapies of AMD is given. According to this AMD currentlyafflicts some 12 million Americans. AMD progressively destroys themacula which is responsible for central vision and color vision. In somecases, deterioration of central vision to fuzzy blur can be rapidoccuring in weeks or months. Two forms of the disease exists called“atrophic” and “exudative”. Although exudative AMD effects only 10% ofthe total AMD population, it accounts for 90% of all AMD-relatedblindness.

Until recently, the only treatment for exudative AMD consisted ofdirecting a powerful laser beam at the harmful blood vessels to heat andcoagulate them. However, only about 15% of patients with exudative AMDhave been eligible for this laser surgery. Other therapies are currentlyin experimental phase. In one approach, called photodynamic therapy, alow-power laser is combined with injection of light-absorbing dye.Another therapy is a more surgical approach and is called “limitedretinal translocation”. In this therapy the leaky vessels are destroyedwith a high-powered laser after separation and rotation of the retinafrom the outer wall of the eye.

U.S. Pat. No. 5,766,591 discribes the use of RGD-containing α_(v)β₃antagonists for the treatment of patients in which neovascularisation inthe retinal tissue occurs. More specifically the use of said antagonistsfor the treatment of patients with diabetic retinopathy, maculardegeneration and neovasular glaucoma is suggested. However, no exampleswith regard to this indications are presented. Concerning to the routeof administration only general information are given. Specificallyintravenous, intraperitoneal, intramuscular, intracavital andtransdermal application is mentioned. In all cases α_(v)β₃ antagonistsare preferred exhibiting selectivity for α_(v)β₃ over other integrinssuch as α_(v)β₅.

WO 97/06791 A1 discribes that α_(v)β₅ antagonists can be used forinhibiting angiogenesis too. Likewise as suggested for α3 antagonists inU.S. Pat. No. 5,766,591 α_(v)β₅ antagonists are suggested for thetreatment of a patient with diabetic retinopathy, macular degenerationand neovasular glaucoma. With regard to the route of administrationintravenous, intraocular, intrasynovial, intramuscular, transdermal andoral application is specifically mentioned.

DESCRIPTION OF THE INVENTION

It has been found that inhibitors of α_(v)β₃ and/or % p, integrinreceptors have particularly useful pharmacological and physicochemicalproperties combined with good tolerability, as, in particular, they canbe used for prophylaxis and treatment of diseases of the eye of apatient resulting from angiogenesis in the eye by injecting theinhibitor into the subTenon's space of the eye.

Accordingly, the invention is directed to a method for prophylaxisand/or treatment of diseases of the eye of a patient resulting fromangiogenesis in the eye comprising injecting into the subTenon's spaceof the eye of the eye of said patient a composition comprising atherapeutically effective amount of an α_(v)β₃ and/or α_(v)β₅ inhibitorsufficient to inhibit angiogenesis of the eye.

Injection into subTenon's space (subTenon's injection) means that themedicament is placed into the space between sciera and Tenon's capsuleusing an appropriate injection device. SubTenon's injection is generallyknown by the person skilled in the art, see, for example, Li HK et al.,Ophthalmology, Vol. 107, No. 1, 41-46 (2000).

Advantageously subTenon's injection is performed using the followingprocedure: (a) prepping and draping the eye in the usual fashion, (b)placing a lid speculum in the eye, (c) making a (ca. 1-2 mm) incisionposterior to the limbus midway between the superior and lateral rectusmusculus through conjunctiva and Tenon's capsule down to bare sclera,(d) grasping the margins of the incision with a forceps and insertingthe injection cannula through the incision io the space between bareslera and both conjunctiva and Tenon's capsule, (e) slowly injecting thecontents of the syringe, advancing the tip of the cannula very slowlyposteriorly and laterally taking care not to tear the capsule orconjunctiva or nearby blood vessels, (f) slowly retracting and finallyremoving the cannula from the globe after applying a cotton tippedapplicator to the injection site just prior to extracting the cannulaand, finally, (g) applying an antibiotic to the injection site.

A therapeutically effective amount is an amount do inhibitor sufficientto produce a measureable inhibition of angiogenesis in the tissue of theeye when injected into the subTenon's space. In general, this is thecase when the α_(v)β₃ and/or α_(v)β₅ inhibitor is used in an amount fromabout 0.5 μg to about 5 mg.

The method of invention is especially usable for prophylaxis and/ortreatment of diabetic retinopathy, macular degeneration, myopia andhistoplasmosis.

In a preferred embodiment of the invention polypeptides containing theamino acid sequence RGD are used as α_(v)β₃ and/or α_(v)β₅ inhibitors inthe method for prophylaxis and/or treatment of eye diseases. Asmentioned above, RGD is the peptide sequence Arg-Gly-Asp(arginine-glycine-aspartic acid) occuring in natural ligands ofintegrins like fibronectin or vitronectin.

Solvable RGD containing linear or cyclic peptides are able to inhibitinteractions of this integrins with their corresponding natural ligands.

The abbreviations for the amino acid residues used hereinafter are shownin the following table: Ala A alanine Arg R arginine Asp D aspartic acidD-homoPhe D-homo-phenylalanine D-Nal D-3-(2-naphthyl)alanine D-PheD-phenylalanine D-Phg D-phenylglycine D-Trp D-tryptophan D-TyrD-tyrosine Gly G glycine 4-Hal-Phe 4-halo-phenylalanine homoPhehomo-phenylalanine Ile I isoleucine Leu L leucine Nal3-(2-naphthyl)alanine Nle norleucine Phe F phenylalanine Phgphenylglycine Trp W tryptophan Tyr Y tyrosine Vat V valine.

Particularly preferred as α_(v)β₃ and/or α_(v)β₅ inhibitors to be usedin the method for prophylaxis and/or treatment of eye diseases arecompounds of formula Icyclo-(Arg-Gly-Asp-D-(A)_(n)E) 1,in which

-   D is D-Phe, Phe, D-Trp, Trp, D-Tyr, Tyr, D-homoPhe, homoPhe, D-NaI,    NaI, D-Phg, Phg or 4-Hal-Phe (D or L form), in which Hal is F, Cl,    Br, I,-   E is Val, Gly, Ala, Leu, Ile or Nle,-   A is alkyl having 1-18 carbon atoms and-   n is 0 or 1-   and also their physiologically acceptable salts.

In formula I alkyl is preferably methyl, ethyl, isopropyl, n-butyl,sec-butyl or tert-butyl.

More particular preferred polypeptides are used as α_(v)β₃ and/orα_(v)β₅ inhibitors in the method of the invention that can be expressedby the subformula Ia, which otherwise corresponds to the formula I butin which

-   D is D-Phe and-   E is Gly, Ala, Val, Leu, Ile or Nle.

Furthermore, particular preference is given to the use of allphysiologically compatible salts of the compounds which come under thesubformula Ia.

Most preferred as active compound in said method arecyclo-(Arg-Gly-Asp-DPhe-Val) and cyclo-(Arg-Gly-Asp-DPhe-NMeVal).

This RGD-containing peptides described by formula I as well as thepeptides specifically mentioned hereinbefore are disclosed in EP 0 770622 A2, the disclosure of which is hereby incorporated to the presentapplication by reference. Accordingly, the meaning of the substituentsof formula I resp. subformula Ia are the same as defined for thesubstituents of subformula Ia resp. subformula Ib as disclosed on page5, line 24 to line 32 resp. page 5, line 33 to line 41 in EP 0 770 662A2.

It has been found that inhibitors of α_(v)β₃ and/or α_(v)β₅ integrinreceptors which are no polypeptides and do not contain the RGD sequencecan also be used for prophylaxis and treatment of diseases of the eye ofa patient resulting from angiogenesis in the eye by injecting theinhibitor into the subTenon's space of the eye.

Therefore, in one further preferred embodiment of the method ofinvention the α_(v)β₃ and/or α_(v)β₅ inhibitors to be used in the methodfor prophylaxis or treatment of eye diseases are compounds of formula II

wherein

-   R¹ is H, alkyl having 1-6 C atoms or benzyl,-   R² is R¹⁰, CO—R¹⁰, COOR⁶, COOR¹⁰, SO₂R⁶ or SO₂R¹⁰,-   R³ is H, Hal, OA, NHR¹⁰, N(R¹⁰)₂, —NH-acyl, —O-acyl, CN, NO₂₁ OR¹⁰,    SR¹⁰, R² or CONHR¹⁰,-   R⁴ is H, ═O, ═S, C₁-C₆-alkyl or acyl,-   R⁵ is NH₂, H₂N—C(═NH) or H₂N—(C═NH)—NH, where the primary amino    groups can also be provided with conventional amino protective    groups or can be mono-, di- or trisubstituted by R¹⁰, CO—R¹⁰, COOR¹⁰    or SO₂R¹⁰, or R⁶.-   R⁷, R⁸ are each independently of one another absent or H.-   R⁷ and R⁸ together are also a bond,-   X, Y are each independently of one another ═N—, —N—, O, S, —CH₂— or    ═C—, with the proviso that at least one of the two definitions X, Y    is ═N—, —N—, O or S,-   W, Z are each independently of one another absent, O, S, NR¹, C(═O),    CONH, NHCO, C(═S)NH, NHC(═S), C(═S), SO₂NH, NHSO₂ or CA═CA′,-   R⁶ is a mono- or binuclear heterocycle which has 1 to 4 N, O and/or    S atoms and can be unsubstituted or mono-, di- or trisubstituted by    Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂, =NH or ═O,-   R⁹ is H, Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO₂, SA, SOA, SO₂A,    SO₂Ar or SO₃H,-   R¹⁰ is H, A, Ar or aralkyl having 7-14 C atoms,-   R¹¹ is H or alkyl having 1-6 C atoms,-   A, A′ are each independently of one another H or unsubstituted or    mono-, di- or tri-R⁹-substituted alkyl or cycloalkyl, each of which    has 1-15 C atoms and in which one, two or three methylene groups can    be replaced by N, O and/or S,-   Ar is unsubstituted or mono-, di- or tri-A- and/or R⁹-substituted    mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N. O    and/or S atoms,-   Hal is F, Cl, Br or I and-   m, n are each independently of one another 0, 1, 2, 3 or 4,-   and the physiologically acceptable salts thereof.

Particularly preferred α_(v)β₃ and/or α_(v)β₅ inhibitors are used in themethod of invention that can be expressed by the subformulae IIa to IIg,which otherwise corresponds to the formula II but in which

in IIa)

-   -   R¹ is H or alkyl with 1-6 C atoms,    -   R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is H₂N—C(═NH) or H₂N—C(═NH)—NH,    -   W, Z are each independently of one another absent. C(═O), NH,        CONH or NHCO,    -   X is —NH—, O or —CH₂—,    -   Y is NH or O,    -   R¹⁰ is H, A or benzyl,    -   R¹¹ is H,    -   A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and    -   m, n are each independently of one another 0, 1 or 2;        in IIb)    -   R¹ is H or alkyl with 1-6 C atoms,    -   R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is R⁶,    -   W, Z are each independently of one another absent, C(═O), NH,        CONH or NHCO,    -   X is —NH—, O or —CH₂—,    -   Y is NH or O,    -   R⁶ is a mono- or binuclear heterocycle which has 1-4 N, O and/or        S atoms and which can be unsubstituted or mono-, di- or        trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂,        ═NH or ═O,    -   R¹⁰ is H, A or benzyl,    -   R¹¹ is H,    -   A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and    -   m, n are each independently of one another 0, 1 or 2;        in IIc)    -   R₁ is H or alkyl with 1-6 C atoms;    -   R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is H₂N—C(═NH) or H₂N—C(═NH)—NH,    -   W, Z are each independently of one another absent, C(═O), NH,        CONH or NHCO,    -   X is —NH—, 0 or —CH₂—,    -   Y is NH or O,    -   A is alkyl with 1-6 C atoms,    -   R¹⁰ is H, alkyl with 1-6 C atoms, camphor-10-yl or benzyl,    -   R¹¹ is H,    -   m, n are each independently of one another 0, 1 or 2;        in IId)    -   R¹ is H or alkyl with 1-6 C atoms,    -   R² is R¹⁰ CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is R⁶,    -   W, Z are each independently of one another absent, C(═O), NH,        CONH or NHCO,    -   X is ═NH—, O or —CH₂—,    -   Y is NH or O,    -   R⁶ is a mono- or binuclear heterocycle which has 1-4 N, O and/or        S atoms and which can be unsubstituted or mono-, di- or        trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂,        =NH or ═O,    -   R¹⁰ is H, alkyl with 14 C atoms, camphor-10-yl or benzyl,    -   R¹¹ is H,    -   A is unsubstituted alkyl with 1-6 C atoms and    -   m, n are each independently of one another 0, 1 or 2;        in IIe)    -   R¹ is H or alkyl with 1-6 C atoms,    -   R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is R⁶,    -   W, Z are each independently of one another absent, C(═O), NH,        CONH or NHCO,    -   X is —NH—, O or —CH₂—,    -   Y is NH or O,    -   R⁶ is 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl,        2H-pyrazol-2-yl, 1H-tetrazol-5-yl,        2-imino-imidazolidin-4-on-5-yl,        1-A-1,5-dihydro-imidazol-4-on-2-yl, pyrimidin-2-yl or        1,4,5,6-tetrahydro-pyrimidin-2-yl,    -   R¹⁰ is H, alkyl with 1-4 C atoms, camphor-10-yl or benzyl,    -   R¹¹ is H,    -   A is unsubstituted alkyl with 1-6 C atoms and    -   m, n are each independently of one another 0, 1 or 2;        in IIf)    -   R¹ is H or alkyl with 1-6 C atoms,    -   R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is H₂N—C(═NH) or H₂N—C(═NH)—NH,    -   W, Z are each independently of one another absent, C(═O), NH,        CONH or NHCO,    -   X is —NH—, O or —CH₂—,    -   Y is NH or O,    -   R¹⁰ is Ar,    -   R¹¹ is H.    -   A is unsubstituted alkyl or cycloalkyl with 1-15 C atoms and    -   m, n are each independently of one another 0, 1 or 2;        in IIg)    -   R¹ is H or alkyl with 1-6 C atoms,    -   R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,    -   R³ is H,    -   R⁴ is H or ═O,    -   R⁵ is R⁶,    -   W, Z are each independently of one another absent, C(═O), NH,        CONH or NHCO,    -   X is —NH—, O or —CH₂—,    -   Y is NH or O,    -   R ⁶ is a mono- or binuclear heterocycle which has 1-4 N, O        and/or S atoms and which can be unsubstituted or mono-, di- or        trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂,        ═NH or ═O,    -   R¹⁰ is Ar,    -   R¹¹ is H,    -   A is unsubstituted alkyl or cycloalkyl with 1-15 C. atoms and    -   m, n are each independently of one another 0, 1 or 2.

The compounds of formula II and subformulae IIa to IIg have beendisclosed in DE 197 05 450 A1, the whole disclosure of which is herebyincorporated to the present application by reference. Accordingly, thesubstituents of formula II resp. subformulae IIa to IIg have the samemeaning as defined for the substituents of formula I resp. subformulaeIa to Ig as disclosed on page 2, lines 3 to 43 resp. page 5, line 58 topage 7, line 30 of DE 197 05 450 A1. The definitions for thesubstituents are given on page 4, line 35 to page 5, line 56 of DE 19705 450 A1.

More particularly preferred one of the following α_(v)β3 and/or α_(v)β₅inhibitors is used in the method of the present invention:

-   (2S)-2-[(R)-camphor-10-sulfonamido]-3-{3,4-dihydro-2-(3-guanidino-propyl)-(2R)-2H-1,4-benzoxazin-3-on-6-yl}propionic    acid;-   (2S)-2-benzyloxycarboxamido-3-(2-guanidinomethyl-1,4-benzodioxan-6-yl)propionic    acid;-   (2S)-2-tert-butyloxycarboxamido-3-[3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-on-6-yl]propionic    acid;-   (2S)-2-benzyloxycarboxamido-3-(2-guanidinoacet-amidomethyl-1,4-benzodioxan-6-yl)propionic    acid;-   (2S)-2-tert-butyloxycarboxamido-33,4-dihydro-2-[N-(2-imidazolyl)-carbamoylmethyl]-2H-1,4-benzox-azin-3-on-6-yl)propionic    acid;-   (2S)-2-tert-butyloxycarboxamido-343,4-dihydro-2-[N-(2-benzimidazolyi)-carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic    acid;-   (2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[2-(2-imino-4-oxoimidazolidin-5-yl)ethyl]-2H-1,4-benzoxazin-3-on-6-yl}propionic    acid;-   (2S)-2-(2,2-dimethylpropyloxycarboxamido)-33,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionic    acid;-   (2S)-2-[(R)-camphorsulfonamido]-3-43,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic    acid-   and their physiologically acceptable salts.

Most preferred are

-   (2S)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoyl-ethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionic    acid and-   (2S)-2-[(R)-camphorsulfonamido]-3-{3,4-dihydro-2-[N-(2-benzimidazolyl)-carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionic    acid:

In one further preferred embodiment of the method of invention theα_(v)β₃ and/or α_(v)β₅ inhibitors to be used in the method forprophylaxis or treatment of eye diseases are compounds of formula III

in which

-   R is CH₂OR¹⁰, COOR¹⁰, CONHR¹⁰ or CON(R¹²)₂,-   R² is R¹⁰, CO—R¹⁰, CO—R⁶, COOR⁶, COOR¹⁰, SO₂R⁶, SO₂R¹, CONHR⁶,    CON(R⁶)₂, CONHR¹⁰ or CON(R¹²)₂,-   R³ is H, Hal, NHR¹⁰, N(R¹²)₂, NH-acyl, —O-acyl, CN, NO₂, OR¹⁰, SR¹⁰,    SO₂R¹⁰, SO₃R¹′, COOR¹⁰, CONHR⁶, CON(R⁶)₂, CONHR¹⁰ or CON(R¹²)₂,-   R⁴ is H, A, Ar or aralkylene having 7-14 C atoms,-   R⁵ is NH₂, H₂N—C(═NH) or H₂N—(C═NH)—NH, where the primary amino    groups can also be provided with conventional amino protective    groups, or can be mono- di- or trisubstituted by R¹⁰, CO—R¹⁰, COOR¹⁰    or SO₂R¹⁰, or R⁶—NH—,-   R⁶ is a mono- or binuclear heterocycle having 1 to 4 N, O and/or S    atoms, which can be unsubstituted or mono-, di- or trisubstituted by    Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂, =NH or ═O,-   R⁷, R⁸ in each case independently of one another is absent or is H,-   R⁷ and R⁸ together are also a bond,-   Z is absent, O, S, NH, NR¹, C(═O), CONH, NHCO, C(═S)NH, NHC(═S),    C(═S), SO₂NH, NHSO₂ or CA═CA′,-   R⁹ is H, Hal, OR¹¹, NH₂, NHR¹², N(R¹²)₂, NHAcyl, OAcyl, CN, NO₂,    SR¹¹, SOR¹², SO₂R¹² or SO₃H,-   R¹⁰ is H, A, Ar or aralkylene having 7-14 C atoms,-   R¹¹ is H or alkyl with 1-6 C atoms,-   R¹² is alkyl having 1-6 C atoms,-   A is H or alkyl having 1-15 C atoms or cycloalkyl having 3-15 C    atoms, which is unsubstituted or is mono-, di- or trisubstituted by    R⁹ and in which one, two or three methylene groups can also be    replaced by N, O and/or S,-   Ar is a mono- or binuclear aromatic ring system having 0, 1, 2, 3 or    4 N, O and/or S atoms, which is unsubstituted or mono-, di- or    trisubstituted by A and/or R⁹,-   Hal is F, Cl, Br or I,-   m, n in each case independently of one another are 0, 1, 2, 3 or 4,-   and their physiologically acceptable salts and solvates.

In this embodiment of the method of the present invention particularlypreferred α_(v)β₃ and/or α_(v)β₅ inhibitors are used that can beexpressed by the subformulae IIIa to IIIn, which otherwise correspond toformula III but in which

in IIIa)

-   -   R³ is H;        in IIIb)    -   R³ is H and    -   R² is COOR¹⁰ or SO₂R¹⁰;        in IIIc)    -   R³ is H,    -   R² is COOR¹⁰ or SO₂R¹⁰ and    -   R¹⁰ is H, A, Ar or aralkylene having 7-14 C atoms;        in IIId)    -   m is 0;        in IIIe)    -   m is 0 and    -   R³ is H;        in IIIf)    -   R³ is H,    -   R² is COOR¹⁰ or SO₂R¹⁰ and    -   m is 0;        in IIIg)    -   R³ is H,    -   R² is COOR¹⁰ or SO₂R¹⁰ and    -   R¹⁰ is H, A, Ar or aralkylene with 7-14 C atoms and    -   m is O;        in IIIh)    -   R³ is H,    -   R² is COOR¹⁰ or SO₂R¹⁰ and    -   R¹⁰ is H, A, Ar or aralkylene having 7-14 C atoms and    -   A is H or unsubstituted alkyl having 1-15 C atoms or cycloalkyl        having 3-15 C atoms;    -   Ar is phenyl or naphthyl and    -   m is 0;        in IIIi)    -   R⁶ is a mono- or binuclear heterocycle having 1 to 4 N atoms,        which can be unsubstituted or mono-, di- or trisubstituted by        Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂, ═NH or ═O,        in IIIj)    -   R³ is H,    -   R² is COOR¹⁰ or SO₂R¹ and    -   R¹⁰ is H, A, Ar or aralkylene having 7-14 C atoms and    -   m is 0;    -   R⁶ is a mono- or binuclear heterocycle having 1 to 4 N atoms,        which can be unsubstituted or mono-, di- or trisubstituted by        Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂, ═NH or ═O;        in IIIk)    -   Z is absent;        in IIIl)    -   Z is absent and    -   R³ is H;        in IIIm)    -   Z is absent,    -   R³ is Hand    -   R² is COOR¹⁰ or SO₂R¹⁰;        in IIIn)    -   Z is absent,    -   R³ is H,    -   R⁴ is H,    -   R² is COOR¹⁰ or SO₂R¹⁰;    -   R¹⁰ is H, A, Ar or aralkylene having 7-14 C atoms, R⁶ is a mono-        or binuclear heterocycle having 1 to 4 N atoms, which can be        unsubstituted or mono-, or risubstituted by Hal, A, —CO-A, OH,        CN, COOH, COOA, CONH₂, NO₂, ═NH or ═O,    -   A is H or unsubstituted alkyl having 1-6 C atoms,    -   Ar is phenyl or naphthyl and    -   m is 0.

The compounds of formula III and subformulae IIIa to IIIn have beendisclosed in WO 00/26212 A1, the whole disclosure of which isincorporated to the present application by reference. Accordingly, thesubstituents of formula III resp. subformulae IIIa to IIIn have the samemeaning as defined for the substituents of formula I resp. subformulaeIa to In as disclosed on page 1, line 5 to page 2, line 31 resp. page13, line 20 to page 15, line 6 of WO 00/26212 A1. The definitions forthe substituents are given on page 8, line 18 to page 13, line 10 of WO00/26212 A1.

More particularly preferred one of the following α_(v)β₃ and/or α_(v)β₅inhibitors is used in this embodiment of the method of the presentinvention:

-   (2S)-3-[2-(3-aminopropyl)-4-oxo4H-chromen-6-yl]-2-(2.2-dimethylpropoxycarboxamido)-propionic    acid;-   (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic    acid;-   (2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]4-oxochroman-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic    acid;-   (2S)-3-{2-[3-(pyrid    in-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic    acid;-   (2S)-3-{2-[3-(1H-benzimidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionic    acid;-   (2S)-3{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylsulfonamidopropionic    acid;-   (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-(2,4,6-trimethylphenyl)sulfonamidopropionic    acid or their physiologically acceptable salts and solvates.

Most preferred are

-   (2S)-3{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}-2-butylsulfonamidopropionic    acid and-   (2S)-3-{2-[3-(pyridin-2-ylamino)propyl]4-oxo4H-chromen-6-yl}-2-(2,4,6-trimethylphenyl)sulfonamidopropionic    acid.

In one further preferred embodiment of the method of invention theα_(v)β₃ and/or α_(v)β₅ inhibitors to be used in the method forprophylaxis or treatment of eye diseases are compounds of formula IV

wherein

-   A and B are each independently of one another O, S, NH, NR⁷, CO,    CONH, NHCO or directly bond,-   X is alkylene having 1-2 C atoms, which is unsubstituted or    monosubstituted by R⁴ or R⁵ or a direct bond,-   R¹ is H, Z or —(CH)_(o)—Ar,-   R² is H, R⁷ or —C(O)Z,-   R³ is NHR⁶, —NR⁶—C(═NR⁶)—NHR⁶, —C(═NR⁶)—NHR⁶, —NR⁶—C(═NR⁹)—NHR⁶,    —C(═NR⁹)—NHR⁶ or Het,-   R⁴ or R⁵ are each indipendently of one another H, oxo, R⁷,    —(CH₂)_(o)—Ar, —C(O)—(CH₂)_(o)—Ar, —C(O)—(CH2)₆—R⁷,    —C(O)—(CH₂)_(o)-Het, Het,-   NHR⁶, NHAr, NH-Het, OR⁷, OAr, OR⁶ or O-Het,-   R⁶ is H, —C(O)R⁷, —C(O)—Ar, R⁷, COOR⁷, COO—(CH₂)_(o)—Ar, SO₂—Ar,    SO₂R⁷ or SO₂-Het,-   R⁷ is alkyl having 1 to 10 C atoms or cycloalkyl having 1 to 10 C    atoms,-   R⁸ is Hal, NO₂, CN, Z, —(CH₂)_(o)—Ar, COOR¹, OR¹, CF₃, OCF₃,-   SO₂R¹, NHR¹, N(R¹)₂, NH—C(O)R¹, NHCOOR¹or C(O)R¹,-   R⁹ is CN or NO₂,-   Z is alkyl having 1 to 6 C atoms,-   Ar is aryl, which is unsubstituted or substituted by R⁸,-   Hal is F, Cl, Br or I,-   Het is saturated, partly of fully saturated mono- or bicyclic    heterocyclic ring system having 5 to 10 atoms, which can contain 1    or 2 N atoms and/or 1 or 2 S or O atoms and wherein the heterocyclic    ring system can be mono- or disubstituted by R⁸,-   Het¹ is a mono or bicyclic aromatic heterocyclic ring system having    1 to 4 N atoms, which can be unsubstituted or mono- or disubstituted    by Hal, R⁷, OR⁷, CN, NHZ or NO₂,-   n is 0, 1 or 2-   m is 0, 1, 2, 3, 4, 5 or 6,-   o is 0, 1 or 2-   as well as their physiologically acceptable salts and solvates.

In this embodiment of the method of invention particularly preferredα_(v)β₃ and/or α_(v)β₅ inhibitors are used that can be expressed by thesubformulae IVa to IVi, which otherwise correspond to formula IV but inwhich

in IVa

-   -   X is a direct bond        in IVb    -   X is a direct bond,    -   R² is H.    -   R⁵ is H and    -   R⁴ is Ar        in IVc    -   X is a direct bond,    -   R⁵ is H and    -   R⁴ is Ar or Het;        in IVd    -   X is a direct bond,    -   R⁵ is H.    -   B is O,    -   A is NH,    -   n is O,    -   m is 3 or 4,    -   R³ is Het and    -   R⁴ is Ar        in IVe    -   X is a direct bond    -   R⁵ is H,    -   B is O,    -   A is NH,    -   n is 0,    -   m is 3 or 4 and    -   R³ is Het        in IVf    -   X is methylene, which is unsubstituted or substituted by Ar,    -   R² is H,    -   R⁵ is H oder Ar and    -   R⁴ is oxo        in IVg    -   X is methylene,        in IVh    -   X is methylene,    -   R⁴ is H or Ar,    -   R⁵ is H or Ar and    -   R² is H;        in IVi    -   X is methylene,    -   R⁴ is H or Ar,    -   R⁵ is H or Ar,    -   B is O,    -   A is NH,    -   n is 0,    -   m is 3 or 4    -   R³ is Het and    -   R² is H

More particularly preferred the α_(v)β₃ and/or α_(v)β₅ inhibitoraccording to formula IV to be used in the method of the presentinvention is:

-   3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic    acid;-   3-phenyl-3-{6-[4-(pyridine-2-ylamino)-butoxy]-1H-indole-3-yl}-propionic    acid;-   3-phenyl-3-{5-[4-(pyridine-2-ylamino)-butoxy]-1H-indole-3-yl}-propionic    acid;-   3-phenyl-3-{5-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic    acid;-   3-phenyl-3-[6-(pyridine-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic    acid;-   3-phenyl-3-[6-(benzimidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic    acid-   3-phenyl-3-[6-(imidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionic    acid or-   3-Benzo[1,2,5]thiadiazol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-1H-indol-3-yl}-propionic    acid-   as well as their physiologically acceptable salts and solvates.

Most preferred the α_(v)β₃ and/or α_(v)β₅ inhibitor according to formulaIV to be used in the method of the present invention is

-   3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionic    acid or-   3-Benzo[1,2,5]thiadiazol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-1H-indol-3-yl}-propionic    acid.

This compounds as well as the compounds of formula IV and subformulaeIVa to IVi are disclosed in copending german patent application no. 10006 139.7, the whole disclosure of which is hereby incorporated to thepresent application by reference. Accordingly, the substituents offormula IV and subformulae IVa to IVi have the same meaning as definedfor the substituents of formula I resp. subformulae Ia to li asdisclosed on page 1, line 3 to page 2, line 13 resp. page 17, line 4 topage 20, line 9 of german patent application no. 100 06 139.7. Thedefinitions for the substituents are given on page 9, line 6 to page 16,line 28 of german patent application no. 100 06 139.7.

The particular suitability of the compounds as described hereinbeforefor using in the method of treatment of eye diseases was experimentallyconfirmed for some representative compounds.

It is a further object of the invention to provide a compositionsuitable for the method for prophylaxis and treatment of diseases of theeye of a patient resulting from angiogenesis comprising injecting intothe subTenon's space of the eye of said patient a composition comprisinga therapeutically effective amount of an α_(v)β₃ and/or α_(v)β₅inhibitor sufficient to inhibit angiogenesis of the eye.

The formulation used for administration of the compound into thesubTenon's space of the eye can be any form suitable for applicationinto the subTenon's space by injection through a cannula with smalldiameter suitable for injection into the subTenon's space. Examples forinjectable application forms are solutions, suspensions or colloidalsuspensions.

Compositions usable for injection into the subTenon's space contain aphysiologically tolerable carrier together with the relevant agent asdescribed herein, dissolved or dispersed therein as an activeingredient. As used herein, the term “pharmaceutically acceptable”refers to compositions, carriers, diluents and reagents which representmaterials that are capable of administration into the subTenon's spaceof a mammal without the production of undesirable physiological effects.The preparation of a injectable pharmacological composition thatcontains active ingredients dissolved or dispersed therein is wellunderstood in the art and need not be limited based on formulation. Thepreparation can also be emulsified. The active ingredient can be mixedwith excipients which are pharmaceutically acceptable and compatiblewith the active ingredient and in amounts suitable for use in thetherapeutic methods described herein. Suitable excipients are, forexample, water, saline, sorbitol, glycerol or the like and combinationsthereof. In addition, if desired, the composition can contain minoramounts of auxiliary substances such as wetting or emulsifying agents,pH buffering agents, and the like which enhance the effectiveness of theactive ingredient. The composition can also contain viscosity enhancingagents like hyaluronic acid. The therapeutic composition of the presentinvention can include pharmaceutically acceptable salts of thecomponents therein. Pharmaceutically acceptable salts include the acidaddition salts that are formed with inorganic acids such as, forexample, hydrochloric or phosphoric acids, or such organic acids asacetic, tartaric, mandelic and the like. Salts formed with the freecarboxyl groups can also be derived from inorganic bases such as, forexample, sodium, potassium, ammonium, calcium or ferric hydroxides, andsuch organic bases as isopropylamine, trimethylamine, 2-ethylaminoethanol, histidine, procaine and the like. Particularly preferred is theHCl salt.

Physiologically tolerable carriers are well known in the art. Exemplaryof liquid carriers are sterile aqueous solutions that contain nomaterials in addition to the active ingredients and water, or contain abuffer such as sodium phosphate at physiological pH value, physiologicalsaline or both, such as phosphate-buffered saline. Still further,aqueous carriers can contain more than one buffer salt, as well as saltssuch as sodium and potassium chlorides, sorbitol and other solutes.

Depending from the application form the active compound liberates in animmediate or a sustained release manner. A sustained release formulationis preferred because the injection frequency can be reduced.

One possibility to achieve sustained release kinetics is embedding orencapsulating the active compound into nanoparticles. Nanoparticles canbe administrated as powder, as powder mixture with added excipients oras suspensions. Colloidal suspensions of nanoparticles are preferredbecause they can easily be administrated through a cannula with smalldiameter. Nanoparticles are particles with a diameter from about 5 nm toup to about 1000 nm. The term “nanoparticles” as it is used hereinafterrefers to particles formed by a polymeric matrix in which the activecompound is dispersed, also known as “nanospheres”, and also refers tonanoparticles which are composed of a core containing the activecompound which is surrounded by a polymeric membrane, also known as“nanocapsules”. For administration into the subTenon's space of the eyenanoparticles are preferred having a diameter from about 50 nm to about500 nm, in particular from about 100 nm to about 200 nm.

Nanoparticles can be prepared by in situ polymerization of dispersedmonomers or by using preformed polymers. Since polymers prepared in situare often not biodegradable and/or contain toxicological seriousbyproducts nanoparticles from preformed polymers are preferred.Nanoparticles from preformed polymers can be prepared by differenttechniques, i.e. by emulsion evaporation, solvent displacement,salting-out and by emulsification diffusion.

Emulsion evaporation is the classical technique for preparation ofnanoparticles from preformed polymers. According to this technique, thepolymer and the active compounds are dissolved in a water-immiscibleorganic solvent, which is emulsified in an aqueous solution. The crudeemulsion is then exposed to a high-energy source such as ultrasonicdevices or passed through high pressure homogenizers or microfluidizersto reduce the particle size. Subsequently the organic solvent is removedby heat and/or vacuum resulting in formation of the nanoparticles with adiameter of about 100 nm to about 300 nm. Usually, methylene chlorideand chloroform are used as organic solvent because of their waterinsolubility, good solubilizing properties, easy emulsification and highvolatility. These solvents are, however, critical in view of theirphysiological tolerability. Moreover, the high shear force needed forparticle size reduction can lead to damage of polymer and/or the activecompound.

The solvent displacement process was firstly described in EP 0 274 961A1. In this process the active compound and the polymer are dissolved inan organic solvent which is miscible with water in all proportions. Thissolution is introduced in an aqueous solution containing a stabilizerunder gentle agitation resulting in spontaneous formation ofnanoparticles. Examples for suitable organic solvents and stabilizer areacetone or ethanol resp. polyvinyl alcohol. Advantageously chlorinatedsolvents and shear stress can be avoided. The mechanism of formation ofnanoparticles has been explained by interfacial turbulence generatedduring solvent displacement (Fessi H. et al., Int. J. Pharm. 55 (1989)R1-R4). Recently, a solvent displacement technique was disclosed by WO97/03657 A1, in which the organic solvent containing the active compoundand the polymer is introduced into the aqueous solution withoutagitation.

The salting-out technique was firstly described in WO 88/08011 A1. Inthis technique a solution of a water-insoluble polymer and an activecompound in a water-soluble organic solvent, especially acetone, ismixed with a concentrated aqueous viscous solution or gel containing acolloidal stabilizer and a salting-out agent. To the resultingoil-in-water emulsion water is added in a quantity sufficient to diffuseinto the aqueous phase and to induce rapid diffusion of the organicsolvent into the aqueous phase leading to interfaciale turbulence andformation of nanoparticles. The organic solvent and the salting-outagent remaining in the suspension of nanoparticles are subsequentlyeliminated by repeated washing with water. Alternatively, the solventand salting-out agent can be eliminated by cross-flow filtration.

In emulsification-diffusion process the polymer is dissolved in awater-saturated partially water-soluble organic solvent. This solutionis mixed with an aqueous solution containing a stabilizer resulting inan oil-in-water emulsion. To this emulsion water is added causing thesolvent to diffuse into the aqueous external phase accompanied withformation of nanoparticles. During particle formation each emulsiondroplet leads to several nanoparticle. As this phenomenon cannot befully explained by convection effect caused by interfacial turbulence,it has been proposed that diffusion of organic solvent from the dropletsof the crude emulsion carries molecules of active compound and polymerphase into the aqueous phase resulting in supersaturated local regions,from which the polymer aggregates in the form of nanoparticles(Quintanar-Guerrero D. et al. Colloid. Polym. Sci. 275 (1997) 640-647).Advantageously, pharmaceutically acceptable solvents like propylenecarbonate or ethyl acetate can be used as organic solvents.

With the methods described above nanoparticles can be formed withvarious types of polymers. For use in the method of the presentinvention, which involves injection of the formulation into thesubTenon's space of the eye, nanoparticles made from biocompatiblepolymers are preferred. The term “biocompatible” refers to materialwhich, after introducing in a biological environment, have no seriouseffects to the biological environment. From biocompatible polymers thosepolymers are especially preferred which are also biodegradable. The term“biodegradable” refers to material which, after introducing in abiological environment, is enzymatically or chemically degraded intosmaller molecules which can be eliminated subsequently.

Biodegradable polymers are well known by the person skilled in the art.Examples are polyesters from hydroxycarboxylic acids such as poly(lacticacid) (PLA), poly(glycolic acid) (PGA), polycaprolactone (PCL),copolymers of lactic acid and glycolic acid (PLGA), copolymers of lacticacid and caprolactone, polyepsilon caprolactone, polyhyroxy butyric acidand poly(ortho)esters, polyurethanes, polyanhydrides, polyacetals,polydihydropyrans, polycyanoacrylates, natural polymers such as alginateand other polysaccharides including dextran and cellulose, collagen andalbumin.

Liposomes are a further drug delivery system which is easily injectable.Accordingly, in the method of invention the active compounds can also beadministered into the subTenon's space of the eye in the form of aliposome delivery system. Liposomes are well-known by a person skilledin the art. Liposomes can be formed from a variety of phospholipids,such as cholesterol, stearylamine of phosphatidylcholines. Liposomesbeing usable for the method of invention encompass all types ofliposomes including, but not limited to, small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles.

1. A method for prophylaxis and/or treatment of diseases of the eye of apatient resulting from angiogenesis in the eye comprising injecting intothe subTenon's space of the eye of said patient a composition comprisinga therapeutically effective amount of an α_(v)β₃ and/or α_(v)β₅inhibitor sufficient to inhibit angiogenesis of the eye
 2. A method ofclaim 1 wherein the α_(v)β₃ and/or α_(v)β₅ inhibitor is a RGD-containingpolypeptide
 3. A method of claim 2 wherein said polypeptide is acompound of formula Icyclo-(Arg-Gly-Asp-D-(A)_(n)E) I, in which D is D-Phe, Phe, D-Trp, Trp,D-Tyr, Tyr, D-homoPhe, homoPhe, D-NaI, NaI, D-Phg, Phg or 4-Hal-Phe (Dor L form), E is Val, Gly, Ala, Leu, Ile or Nle and A is alkyl having1-18 carbon atoms, n 0 or 1 and also their physiologically acceptablesalts
 4. A method of claim 2 wherein said polypeptide is a compound asexpressed by subformula Ia, which otherwise correspond to formula I butin which D is D-Phe and E is Gly, Ala, Val, Leu, Ile or Nle.
 5. A methodof claim 2 wherein said polypeptide is cyclo-(Arg-Gly-Asp-DPhe-Val)
 6. Amethod of claim 2 wherein said polypeptide iscyclo-(Arg-Gly-Asp-DPhe-NMeVal)
 7. A method of claim 2 wherein saidtherapeutically efective amount is from about 0.5 μg to 5 mg
 8. A methodof claim 2 wherein said eye disease is diabetic retinopathy
 9. A methodof claim 2 wherein said eye disease is macular degeneration
 10. A methodof claim 2 wherein said eye disease is myopia
 11. A method of claim 2wherein said eye disease is ocular histoplasmosis
 12. A method of claim1 wherein the α_(v)β₃ and/or α_(v)β₅ inhibitor is a compound of formulaII

wherein R¹ is H, alkyl having 1-6 C atoms or benzyl, R² is R¹⁰, CO—R¹⁰,COOR⁶, COOR¹⁰, SO₂R⁶ or SO₂R¹⁰, R³ is H, Hal, OA, NHR¹⁰, N(R¹⁰)₂,—NH-acyl, —O-acyl, CN, NO₂, R⁴ is H, ═O, S, C₁-C₈-alkyl or acyl, R⁵ isNH₂, H₂N—C(═NH) or H₂N—(C═NH)—NH, where the primary amino groups canalso be provided with conventional amino protective groups or can bemono-, di- or trisubstituted by R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰, or R⁶,R⁷, R⁸ are each independently of one another absent or H, R⁷ and R⁸together are also a bond, X, Y are each independently of one another═N—, —N—, O, S, —CH₂— or ═C—, with the proviso that at least one of thetwo definitions X, Y is ═N—, —N—, O or S, W, Z are each independently ofone another absent, O, S, NR¹, C(═O), CONH, NHCO, C(═S)NH, NHC(═S),C(═S), SO₂NH, NHSO₂ or CA═CA′, R⁶ is a mono- or binuclear heterocyclewhich has 1 to 4 N, O and/or S atoms and can be unsubstituted or mono-,di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂,═NH or ═O, R⁹ is H. Hal, OA, NHA, NAA′, NHacyl, Oacyl, CN, NO₂, SA, SOA,SO₂A, SO₂Ar or SO₃H, R¹⁰ is H, A, Ar or aralkyl having 7-14 C atoms, R¹¹is H or alkyl having 1-6 C atoms, A, A′ are each independently of oneanother H or unsubstituted or mono-, di- or tri-R⁹-substituted alkyl orcycloalkyl, each of which has 1-15 C atoms and in which one, two orthree methylene groups can be replaced by N, O and/or S, Ar isunsubstituted or mono-, di- or tri-A- and/or R⁹-substituted mono- orbinuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or Satoms, Hal is F, Ci, Br or I and m, n are each independently of oneanother 0, 1, 2, 3 or 4, or a the physiologically acceptable saltsthereof
 13. A method of claim 12 wherein the α_(v)β₃ and/or α_(v)β₅inhibitor is selected from the group consisting of compounds ofsubformulae IIa to IIg, which otherwise correspond to formula II but inwhich in IIa) R¹ is H or alkyl with 1-6 C atoms, R² is R¹⁰, CO-R¹⁰,COOR¹⁰ or SO₂R¹⁰, R³ is H, R⁴ is H or ═O, R⁵ is H₂N—C(═NH) orH₂N—C(═NH)—NH, W, Z are each independently of one another absent, C(═O),NH, CONH or NHCO, X is —NH—, O or —CH₂—, Y is NH or O, R¹⁰ is H, A orbenzyl, R¹¹ is H, A is unsubstituted alkyl or cycloalkyl with 1-15 Catoms and m, n are each independently of one another 0, 1 or 2; in IIb)R¹ is H or alkyl with 1-6 C atoms, R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,R³ is H, R⁴ is H or ═O, R⁵ is R⁶, W, Z are each independently of oneanother absent, C(═O), NH, CONH or NHCO, X is —NH—, 0 or —CH₂—, Y is NHor O, R⁶ is a mono- or binuclear heterocycle which has 1-4 N, O and/or Satoms and which can be unsubstituted or mono-, di- or trisubstituted byHal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂, ═NH or ═O, R¹⁰ is H, A orbenzyl, R¹¹ is H, A is unsubstituted alkyl or cycloalkyl with 1-15 Catoms and m, n are each independently of one another 0, 1 or 2; in IIc)R¹ is H or alkyl with 1-6 C atoms, R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,R³ is H, R⁴ is H or ═O, R⁵ is H₂N—C(═NH) or H₂N—C(═NH)—NH, W, Z are eachindependently of one another absent, C(═O), NH, CONH or NHCO, X is —NH—,O or —CH₂—, Y is NH or O, A is alkyl with 1-6 C atoms, R¹⁰ is H, alkylwith 1-6 C atoms, camphor-10-yl or benzyl, R¹¹ is H. m, n are eachindependently of one another 0, 1 or 2; in IId) R¹ is H or alkyl with1-6 C atoms, R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰, R³ is H, R⁴ is H or═O, R⁵ is R⁶, W, Z are each independently of one another absent, C(═O),NH, CONH or NHCO, X is ═NH—, O or —CH₂—, Y is NH or O, R⁶ is a mono- orbinuclear heterocycle which has 1-4 N, O and/or S atoms and which can beunsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN,COOH, COOA, CONH₂, NO₂, =NH or ═O, R¹⁰ is H, alkyl with 1-4 C atoms,camphor-10-yl or benzyl, R¹¹ is H, A is unsubstituted alkyl with 1-6 Catoms and m, n are each independently of one another 0, 1 or 2; in IIe)R₁ is H or alkyl with 16 C atoms, R² is R¹⁰, CO—R¹¹, COOR¹⁰ or SO₂R¹⁰,R³ is H, R⁴ is H or ═O, R⁵ is R⁶, W, Z are each independently of oneanother absent, C(═O), NH, CONH or NHCO, X is —NH—, 0 or —CH₂—, Y is NHor O, R⁶ is 1H-imidazol-2yl, thiazol-2-yl, 1H-benzimidazol-2-yl,2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-imino-imidazolidin-4-on-5-yl,1-A-1,5-dihydro-imidazol-4-on-2-yl, pyrimidin-2-yl or1,4,5,6-tetrahydro-pyrimidin-2-yl, R¹⁰ is H, alkyl with 1-4 C atoms,camphor-10-yl or benzyl, R¹¹ is H. A is unsubstituted alkyl with 1-6 Catoms and m, n are each independently of one another 0, 1 or 2; in IIf)R¹ is H or alkyl with 1-6 C atoms, R² is R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰,R³ is H, R⁴ is H or ═O, R⁵ is H₂N—C(═NH) or H₂N—C(═NH)—NH, W, Z are eachindependently of one another absent, C(═O), NH, CONH or NHCO, X is —NH—,O or —CH₂—, Y is NH or O, R¹⁰ is Ar, R¹¹ is H, A is unsubstituted alkylor cycloalkyl with 1-15 C atoms and m, n are each independently of oneanother 0, 1 or 2; in IIg) R¹ is H or alkyl with 1-6 C atoms, R² is R¹⁰,CO—R¹⁰, COOR¹⁰ or SO₂R¹⁰, R³ is H. R⁴ is H or ═O, R⁵ is R⁶, W, Z areeach independently of one another absent, C(═O), NH, CONH or NHCO, X is—NH—, O or —CH₂—, Y is NH or O, R⁶ is a mono- or binuclear heterocyclewhich has 1-4 N, O and/or S atoms and which can be unsubstituted ormono-, di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA,CONH₂, NO₂, =NH or =0, R¹⁰ is Ar, R¹¹ is H, A is unsubstituted alkyl orcycloalkyl with 1-15 C. atoms and m, n are each independently of oneanother 0, 1 or 2
 14. A method according to claim 12 wherein the Op,and/or 405 inhibitor is a compound selected from the group consisting of(2S)-2-[(R)-camphor-10-sulfonamido]-3-{3,4-dihydro-2-(3-guanidinopropyl)-(2R)-2H-1,4-benzoxazin-3-on-6-yl}propionicacid;(2S)-2-benzyloxycarboxamido-3-(2-guanidinomethyl-1,4-benzodioxan-6-yl)propionicacid;(2S)-2-tert-butyloxycarboxamido-3-[3,4-dihydro-2-(2-guanidino-2-oxoethyl)-2H-1,4-benzoxazin-3-on-6-yl]propionicacid;(2S)-2-benzyloxycarboxamido-3-(2-guanidinoacet-amidomethyl-1,4-benzodioxan-6-yl)propionicacid;(2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[N-(2-imidazolyl)-carbamoylmethyl]-2H-1,4-benzox-azin-3-on-6-yl)propionicacid;(2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[N-(2-benzimidazoiyi)carbamoylmetlhyl]-2H-1,4-benzoxazin-3-on-6-yl)propionicacid;(2S)-2-tert-butyloxycarboxamido-3-{3,4-dihydro-2-[2-(2-imino-oxoimidazolidin-5-yl)ethyl]-2H-1,4-benzoxazin-3-on-6-yl}propionicacid;(2S)-2-(2,2-dimethylpropyloxycarboxamido)-3-{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionic;(2S)-2-[(R)-camphorsulfonamido]-3-(3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionicacid and their physiologically acceptable salts
 15. A method accordingto claim 12 wherein the α_(v)β₃ and/or α_(v)β₅ inhibitor is(2S)-2-(2,2-dimethylpropyloxycarboxamido)-3{3,4-dihydro-2-[N-(2-imidazolyl)carbamoylethyl]-(2S)-2H-1,4-benzoxazin-3-on-6-yl}propionicacid or(2S)-2-[(R)-camphorsulfonamido]-3{3,4-dihydro-2-[N-(2-benzimidazolyl)carbamoylmethyl]-2H-1,4-benzoxazin-3-on-6-yl)propionicacid
 16. A method of claim 12 wherein said amount is from about 0.5 μgto 5 mg
 17. A method of claim 12 wherein said eye disease is diabeticretinopathy
 18. A method of claim 12 wherein said eye disease is maculardegeneration
 19. A method of claim 12 wherein said eye disease is myopia20. A method of claim 12 wherein said eye disease is ocularhistoplasmosis
 21. A method of claim 1 wherein the α_(v)β₃ and/orα_(v)β₅ inhibitor is a compound of formula III

in which R¹ is CH₂OR¹⁰, COOR¹⁰, CONHR¹⁰ or CON(R¹²)₂, R² is R¹⁰, CO—R¹⁰,CO-R⁶, COOR⁶, COOR¹⁰, SO₂R⁶, SO₂R¹²)₂, CONHR⁶, CON(R⁶)₂, CONHR¹⁰ orCON(R¹²)₂, R³ is H. Hal, NHR¹⁰, N(R¹²)₂, NH-acyl, —O-acyl, CN, NO₂,OR¹⁰, SR¹⁰, SO₂R¹⁰, SO₃R¹⁰, COOR¹⁰, CONHR⁶, CON(R⁶)₂, CONHR¹⁰ orCON(R¹²)₂, R⁴ is H, A, Ar or aralkylene having 7-14 C atoms, R⁵ is NH₂,H₂N—C(═NH) or H₂N—(C═NH)—NH, where the primary amino groups can also beprovided with conventional amino protective groups, or can be mono- di-or trisubstituted by R¹⁰, CO—R¹⁰, COOR¹⁰ or SO₂R¹¹, or R⁵—NH—, R⁶ is amono- or binuclear heterocycle having 1 to 4 N, O and/or S atoms, whichcan be unsubstituted or mono-, di- or trisubstituted by Hal, A, —CO-A,OH, CN, COOH, COOA, CONH₂, NO₂, =NH or ═O, R⁷, R⁸ in each caseindependently of one another is absent or is H, R⁷ and R⁸ together arealso a bond, Z is absent, O, S, NH, NR¹, C(═O), CONH, NH¹, CO, C(═S)NH,NHC(═S), C(═S), SO₂NH, NHSO₂ or CA═CA′, R⁹ is H, Hal, OR¹¹, NH₂, NHR¹²,N(R¹²)₂, NHAcyl, OAcyl, CN, NO₂, SR¹¹, SOR¹², SO₂R¹² or SO₃H, R¹⁰ is H,A, Ar or aralkylene having 7-14 C atoms, R¹¹ is H or alkyl with 1-6 Catoms, R¹² is alkyl having 1-6 C atoms, A is H or alkyl having 1-15 Catoms or cycloalkyl having 3-15 C atoms, which is unsubstituted or ismono-, di- or trisubstituted by R⁹ and in which one, two or threemethylene groups can also be replaced by N, O and/or S, Ar is a mono- orbinuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or Satoms, which is unsubstituted or mono-, di- or trisubstituted by Aand/or R⁹, Hal is F, Cl, Br or I, m, n in each case independently of oneanother are 0, 1, 2, 3 or 4, and their physiologically acceptable saltsand solvates
 22. A method of claim 21 wherein the α_(v)β₃ and/or α_(v)β₅inhibitor is selected from the group consisting of compounds ofsubformulae IIIa to IIIn, which otherwise correspond to formula III butin which in IIIa) R³ is H; in IIIb) R³ is H and R² is COOR¹⁰ or SO₂R¹⁰;in IIIc) R³ is H, R² is COOR¹⁰ or SO₂R¹⁰ and R¹⁰ is H, A, Ar oraralkylene having 7-14 C atoms; in IIId) m is 0; in IIIe) m is 0 and R³is H; in IIIf) R³ is H, R² is COOR¹⁰ or SO₂R¹⁰ and m is 0; in IIIg) R³is H, R² is COOR¹⁰ or SO₂R¹⁰ and R¹⁰ is H, A, Ar or aralkylene with 7-14C atoms and m is 0; in IIIh) R³ is H, R² is COOR¹⁰ or SO₂R¹⁰ and R¹⁰ isH, A, Ar or aralkylene having 7-14 C atoms and A is H or unsubstitutedalkyl having 1-15 C atoms or cycloalkyl having 3-15 C atoms, Ar isphenyl or naphthyl and m is 0; in IIIi) R⁵ is a mono- or binuclearheterocycle having 1 to 4 N atoms, which can be unsubstituted or mono-,di- or trisubstituted by Hal A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂,═NH or ═O; in IIIj) R³ is H, R² is COOR¹⁰ or SO₂R¹⁰ and R¹⁰ is H, A, Aror aralkylene having 7-14 C atoms and m is 0; R⁶ is a mono- or binuclearheterocycle having 1 to 4 N atoms, which can be unsubstituted or mono-,di- or trisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂,═NH or ═O; in III(k) Z is absent; in IIIl) Z is absent and R³ is H; inIIIm) Z is absent, R³ is Hand R² is COOR¹⁰ or SO₂R¹⁰; in IIIn) Z isabsent, R³ is H, R⁴ is H, R² is COOR¹⁰ or SO₂R¹⁰; R¹⁰ is H. A, Ar oraralkylene having 7-14 C atoms, R¹⁰ is a mono- or binuclear heterocyclehaving 1 to 4 N atoms, which can be unsubstituted or mono-, di- ortrisubstituted by Hal, A, —CO-A, OH, CN, COOH, COOA, CONH₂, NO₂, ═NH or═O, A Is H or unsubstituted alkyl having 1-6 C atoms, Ar is phenyl ornaphthyl and m is 0
 23. A method according to claim 21 wherein theα_(v)β₃ and/or α_(v)β₅ inhibitor is a compound selected from the groupconsisting of(2S)-3-[2-(3-aminopropyl)-4-oxo-4H-chromen-6-yl]-2-(2,2-dimethylpropoxycarboxamido)-propionicacid;(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]4-oxo-4H-chromen-6-yl}-2-(2,2-dimethylpropoxycarboxamido)propionicacid;(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxochroman-6-yl)-2-(2,2-dimethylpropoxycarboxamido)propionicacid;(2S)-3-{2-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}2-(2,2-dimethylpropoxycarboxamido)propionicacid;(2S)-3{2-[3-(1H-benzimidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}2-(2,2-dimethylpropoxycarboxamido)propionicacid;(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl)-2-butylsulfonamidopropionicacid(2S)-32-[3-(pyridin-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}2-(2,4,6-trimethylphenyl)sulfonamidopropionicacid. and their physiologically acceptable salts and solvates
 24. Amethod according to claim 21 wherein the α_(v)β₃ and/or α_(v)β₅inhibitor is a compound selected from the group consisting of(2S)-3-{2-[3-(1H-imidazol-2-ylamino)propyl]-4-oxo-4H-chromen-6-yl}2-butylsulfonamidopropionicacid and(2S)-3-{2-[3-(pyridin-2-ylamino)propyl]4-oxo4H-chromen-6-yl}-2-(2,4,6-trimethylphenyl)sulfonamidopropionicacid
 25. A method of claim 21 wherein said amount is from about 0.5 μgto 5 mg
 26. A method of claim 21 wherein said eye disease is diabeticretinopathy
 27. A method of claim 21 wherein said eye disease is maculardegeneration
 28. A method of claim 21 wherein said eye disease is myopia29. A method of claim 21 wherein said eye disease is ocularhistoplasmosis
 30. A method of claim 1 wherein the α_(v)β₃ and/orα_(v)β₅ inhibitor is a compound of formula IV

wherein A and B are each independently of one another O, S. NH, NR⁷, CO,CONH, NHCO or directly bond, X is alkylene having 1-2 C atoms, which isunsubstituted or monosubstituted by R⁴ or R⁵ or a direct bond, R¹ is H,Z or —(CH₂)_(o)—Ar, R² is H, R⁷ or —C(O)Z, R³ is NHR⁶,—NR⁶—C(═NR⁶)—NHR⁶, —C(═NR⁶)—NHR⁶, —NR⁶—C(═NR⁹)—NHR⁶, —C(═NR⁹)—NHR⁶ orHet¹, R⁴ or R⁵ are each indipendently of one another H, oxo, R⁷,—(CH₂)₀—Ar, —C(O)—(CH₂)_(o)—Ar, —C(O)—(CH₂)₀—R⁷, —C(O)—(CH₂)₀-Het, Het,NHR⁶, NHAr, NH-Het, OR⁷, OAr, OR⁶ or O-Het, R⁶ is H, —C(O)R⁷, —C(O)—Ar,R⁷, COOR⁷, COO—(CH₂)₀—Ar, SO₂—Ar, SO₂R⁷ or SO₂-Het, R⁷ is alkyl having 1to 10 C atoms or cycloalkyl having 1 to 10 C atoms, R⁸ is Hal, NO₂, CN,Z, —(CH)O—Ar, COOR¹, OR¹, CF₃, OCF₃, SO₂R¹, NHR¹, N(R¹)₂, NH—C(O)R¹,NHCOOR¹ or C(O)R¹, R⁹ is CN or NO₂, Z is alkyl having 1 to 6 C atoms, Aris aryl, which is unsubstituted or substituted by R⁸, Hal is F, Cl, Bror I, Het is saturated, partly of fully saturated mono- or bicyclicheterocyclic ring system having 5 to 10 atoms, which can contain 1 or 2N atoms and/or 1 or 2 S or O atoms and wherein the heterocyclic ringsystem can be mono or disubstituted by R⁵, Het¹ is a mono or bicyclicaromatic heterocyclic ring system having 1 to 4 N atoms, which can beunsubstituted or mono or disubstituted by Hal, R⁷W, OR, CN, NHZ or NO₂,n is 0, 1 or 2 m is 0, 1, 2, 3, 4, 5 or 6, o is 0, 1 or 2 as well astheir physiologically acceptable salts and solvates
 31. A methodaccording to claim 30 wherein the α_(v)β₃ and/or α_(v)β₅ inhibitor isselected of the group consisting of compounds of subformulae IVa to IVi,which otherwise correspond to formula IV but in which in IVa X is adirect bond

in IVb X is a direct bond, R² is H, R⁵ is H and R⁴ is Ar

in IVc X is a direct bond, R⁵ is H and R⁴ is Ar or Het; in IVd X is adirect bond, R⁵ is H, B is O, A is NH, n is 0, m is 3 or 4, R³ is Hetand R⁴ is Ar

in IVe X is a direct bond, R⁵ is H, B is O, A is NH, n is 0, m is 3 or 4and R³ is Het

in IVf X is methylene, which is unsubstituted or substituted by Ar, R²is H, R⁵ is H oder Ar and R⁴ is oxo

in IVg X is methylene,

in IVh X is methylene, R⁴ is H or Ar., R⁵ is H or Ar and R² is H; in IViX is methylene, R⁴ is H or Ar, R⁵ is H or Ar, B is O, A is NH, n is 0, mis 3 or 4 R³ is Het and R² is H


32. A method according to claim 30 wherein the α_(v)β₃ and/or α_(v)β₅inhibitor is a compound selected from the group consisting of3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionicacid;3-phenyl-3-{6-[4-(pyridine-2-ylamino)-butoxy]-1H-indole-3-yl}-propionicacid;3-phenyl-35-[4-(pyridine-2-ylamino)-butoxy]-1H-indole-3-yl}-propionicacid;3-phenyl-35-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionicacid;3-phenyl-3-[6-(pyridine-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionicacid;3-phenyl-3-[6-(benzimidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionicacid;3-phenyl-3-[6-(imidazole-2-yl-amidocarboxymethoxy)-indole-3-yl]-propionicacid or3-Benzo[1,2,5]thiadiazol-5-yl-3-{6-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-1H-indol-3-yl)propionicacid as well as their physiologically acceptable salts and solvates 33.A method of claim 30 werein wherein the α_(v)β₃ and/or α_(v)β₅ inhibitoris3-phenyl-3-{6-[3-(pyridine-2-ylamino)-propoxy]-1H-indole-3-yl}-propionicacid or3-Benzo[1,2,5]thiadiazol-5-yl-36-[2-(6-methylamino-pyridin-2-yl)-ethoxy]-1H-indol-3-yl}-propionicacid
 34. A method of claim 30 wherein said amount is from about 0.5 μgto 5 mg
 35. A method of claim 30 wherein said eye disease is diabeticretinopathy
 36. A method of claim 30 wherein said eye disease is maculardegeneration
 37. A method of claim 30 wherein said eye disease is myopia38. A method of claim 30 wherein said eye disease is ocularhistoplasmosis
 39. A method for prophylaxis and/or treatment of diseasesof the eye of a patient resulting from angiogenesis in the eyecomprising injecting into the subTenon's space of the eye of saidpatient a composition comprising nanoparticles containing atherapeutically effective amount of an α_(v)β₃ and/or α_(v)β₅ inhibitorsufficient to inhibit angiogenesis of the eye
 40. A method of claim 39characterized in that the nanoparticles contain a biocompatible polymer41. A method of claim 39 characterized in that the nanoparticles containa biodegradable polymer
 42. A method of claim 41 characterized in thatthe polymer is poly(lactic acid) (PLA), poly(glycolic acid) (PGA),polycaprolactone (PCL), a copolymer of lactic acid and glycolic acid(PLGA), a copolymer of lactic acid and caprolactone, polyepsiloncaprolactone, polyhyroxy butyric acid, a poly(ortho)ester, apolyurethane, a polyanhydride, a polyacetal, a polydihydropyran or apolycyanoacrylate
 43. A method of claim 39 characterized in that thecomposition comprise a liquid medium wherein the nanoparticles are beingdispersed thereby forming a colloidal suspension
 44. A method of claim39, characterized in that the nanoparticles have a diameter from about10 nm to about 500 nm
 45. A method of claim 39 characterized in that thenanoparticles have a diameter from about 100 nm to about 200 nm
 46. Amethod of claim 39 characterized in that the nanoparticles have beenprepared by solvent displacement